Journal
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Volume 85, Issue 11, Pages 2499-2511Publisher
WILEY
DOI: 10.1111/bcp.14054
Keywords
anticancer drugs; drug metabolism; drug safety; histone deacetylase inhibitor; liver disease
Categories
Funding
- NATIONAL CANCER INSTITUTE [ZIABC011078] Funding Source: NIH RePORTER
- NCATS NIH HHS [UL1 TR001855] Funding Source: Medline
- NCI NIH HHS [P30-CA47904, P30 CA022453, U01-CA099168, UM1-CA186690, P30 CA047904, UM1 CA186690, R50 CA211241, UM1 CA186717, HHSN261200800001E] Funding Source: Medline
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Aims The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic. Methods We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction. Results Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m(2)/day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m(2) in patients with normal liver function, compared to 542, 505 and 444 mL/min/m(2) in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease. Conclusion While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.
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